Aldosterone induces myofibroblastic transdifferentiation and collagen gene expression through the Rho-kinase dependent signaling pathway in rat mesangial cells.
There is accumulating evidence indicating the role of aldosterone in the pathogenesis of hypertension and renal injury. In this study, we investigated the role of the Rho-kinase dependent signaling pathway in aldosterone-induced myofibroblastic transdifferentiation and collagen gene expression in rat mesangial cells (RMCs). Stimulation with aldosterone (1 nmol/L) significantly increased phosphorylation of myosin phosphatase target subunit-1 (MYPT-1), a marker of Rho-kinase activity, with a peak at 20 min in RMCs. Pre-incubation with a selective mineralocorticoid receptor antagonist, eplerenone (10 micromol/L), or a specific Rho-kinase inhibitor, Y27632 (10 micromol/L), attenuated the aldosterone-induced increase in MYPT-1 phosphorylation. Aldosterone also induced hypertrophy in RMCs, accompanied by an increase in actin polymerization and expression of alpha-smooth muscle actin (alpha-SMA), a myofibroblastic transdifferentiation marker. Collagen type I, III and IV mRNA levels were also increased with aldosterone stimulation. Pre-treatment with eplerenone or Y27632 prevented the aldosterone-induced cell hypertrophy, actin polymerization, the increase in alpha-SMA expression and the increases of collagen type I, III, IV mRNA levels in RMCs. These results suggest that aldosterone-induced mesangial cell hypertrophy is associated with cell transformation, leading to an increase in collagen gene expression via the Rho-kinase dependent signaling pathway.
Diah
Suwarni
S
Department of Pharmacology Faculty of Medicine, Kagawa University, 761-0793, Japan.
Zhang
Guo-Xing
GX
Nagai
Yukiko
Y
Zhang
Wei
W
Gang
Liu
L
Kimura
Shoji
S
Hamid
Mas R W Abdul
MR
Tamiya
Takashi
T
Nishiyama
Akira
A
Hitomi
Hirofumi
H
D000450:Aldosterone / Q000494:pharmacology*; D000577:Amides / Q000494:pharmacology; D000818:Animals; D054338:Cell Transdifferentiation / Q000187:drug effects* / Q000235:genetics; D003094:Collagen / Q000235:genetics*; D000077545:Eplerenone; D005786:Gene Expression Regulation / Q000187:drug effects; D006984:Hypertrophy; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D024510:Muscle Development / Q000187:drug effects* / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018161:Receptors, Mineralocorticoid / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013148:Spironolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D054460:rho-Associated Kinases / Q000378:metabolism / Q000502:physiology*
D000577:Amides; D000451:Mineralocorticoid Receptor Antagonists; D011725:Pyridines; D018161:Receptors, Mineralocorticoid; C108830:Y 27632; D013148:Spironolactone; D000450:Aldosterone; D000077545:Eplerenone; D003094:Collagen; D054460:rho-Associated Kinases